One of the key issues in cancer immunotherapy is to identify the dominant escape mechanisms during different phases of tumor growth and to devise ways to overcome them. We have identified B7x as a poorly characterized member of the B7 family of T cell costimulation and coinhibition. Our clinical data have revealed that aberrant expression of B7x is observed in a variety of human cancers and is often associated with poor clinical outcome. The hypothesis of this project is that B7x is a critical immune evasion pathway within the tumor microenvironment and blockade of this pathway generates therapeutic tumor immunity. Guided by our published clinical research with cancer patients and our strong preliminary data with murine tumor models, this hypothesis will be tested by pursuing three specific aims: 1) Elucidation of the functional consequence of tumor-expressed B7x in disease progression; 2) Determination of mechanistic contribution of host cell-expressed B7x to tumor progression; and 3) Generation of therapeutic tumor immunity by targeting the B7x pathway. We have generated a number of novel tools and have assembled a multi-disciplinary team with complementary skill sets, which provides us with unique opportunities to address challenges and realize goals. The outcomes of this research will provide novel insights into immune evasion mechanisms of the B7x pathway in the tumor microenvironment and provide the basis for future clinical design of a new immunotherapy.